Steroid hormones stimulate growth, maturation and the development of new biochemical capacities in their endocrine target organs and are keys to understanding multiple diseases. They act by binding to their cognate nuclear receptors and recruiting a series of coregulator (coactivator/corepressor) proteins that carry out all substeps of transcription and also influence non-nuclear functions of the hormones. Although the basic overall pathways by which sex steroids exert their biochemical actions are known, the detailed mechanisms by which they act to regulate functions in normal and pathological tissues remain elusive. For example, in the past 12 years, we have discovered the existence of NR coactivators, determined how they function at various steps of chromatin remodeling and transcription, and realized their enormous potential in influencing the initiation and progression of disease. Now, we need to understand the mechanisms by which coactivators function in precise detail. For example, how does one coactivator perform so many different important functions in mammalian tissues? How does a coactivator become `activated'to form distinct multimeric coactivator complexes for cellular functions? How does a coactivator differentially bind to NRs (or other transcription factors) for transcriptional activation at select promoters? How does a coactivator direct distinct subreactions of transcription (eg., chromatin remodeling, transcriptional initiation, RNA chain elongation, RNA splicing, termination, etc.)? How can one coactivator participate in regulating molecular substeps of transcription on one hand, and then on the other hand, function in totally different cellular compartments to control mRNA translation, mitochondrial biology, or membrane initiated cell motility? Finally, how does the same coregulator function as a `coactivator'in certain instances, and as a `corepressor'in other instances? Even more perplexing, how can a specific coactivator function as a stimulator (eg., oncogene) in certain cell contexts and a repressor (eg., tumor suppressor) in others? We are excited to have recently discovered that the secret to these functions lies in the `posttranslational modification (PTM) coding'of coactivators. It is our belief that understanding this PTM coding, will disclose the mechanistic secrets of all normal function and the information required for the diagnosis and treatment and prevention of myriad endocrine and reproductive diseases. PUBLIC HEALTH RELEVANCE: Steroid hormones stimulate growth, maturation and the development of new biochemical capacities in their endocrine target organs and are keys to understanding multiple diseases. They act by binding to their cognate nuclear receptors and recruiting a series of coregulator (coactivator/corepressor) proteins that carry out all substeps of transcription and also influence non-nuclear functions of the hormones.